1. Field of the Invention
This invention relates to a process for synthesizing macrocyclic chelates. More specifically, this invention relates to 2-substituted 1,4,7,10-Tetraazacyclododecane-N,N',N",N'"-tetraacetic acid, and 2-substituted 1,4,7,10-Tetraazacyclododecane, and analog macrocycles.
2. Description of the Background Art
Macrocycles have been studied for their usefulness as chelates for numerous metal ions that have therapeutic, diagnostic, or other uses. A macrocycle of particular usefulness as a chelate is the 1,4,7,10-Tetraazacyclododecane-N,N,N,N-tetraacetic acid (DOTA). DOTA compounds have been linked to biomolecules to form delivery systems for the chelated metal ion to specific sites within an organism. Processes to synthesize these compounds typically result in yields of 1 percent or less of the desired compound from the starting material.
U.S. Pat. No. 4,678,667 to Meares et al., discloses a macrocyclic bifunctional chelating agent. The chelating agents of this disclosure can include DOTA compound that is a Cu(II) chelate. The usefulness of the chelating agent is limited to the effects of the copper metal ion. The process of this disclosure gives low and not always reproducible results.
An earlier U.S. Pat. No. 4,622,420 to Meares et al. disclosed bifunctional chelating agents of the acyclic ligand ethylene diamene N,N',N",N'"-tetraacetic acid (EDTA) useful for binding metals other than copper such as Indium. These compounds are useful for imaging of tumors.
U.S. Pat. No. 4,652,519 to Warshawsky et al., discloses bifunctional chelating agents and process for their production. The compounds disclosed in this patent are analogoues of EDTA. These compounds are used to chelate metal ions and are linked to haptens to provide specific site selection within an organism. The compounds of this patent are offered to provide an improved substituent for the EDTA compounds such as those disclosed in the Meares et al. patent discussed above.
U.S. Pat. Nos. 4,454,106 and 4,472,509 to Gansow et al., respectively disclose the use of metal chelate conjugated monoclonal antibodies and the specific metal chelate conjugated monoclonal antibodies. These disclosures provide compounds and methods for treating cellular disorders. Radiometal chelate conjugated monoclonal antibodies specific to a target cell are used to deliver alpha, beta, or Auger electron emitting metal ions. These disclosures are not related to DOTA compounds.
The value of having a ligand conjugate to chelate metal ions for therapeutic, diagnostic, or other uses is of commercial importance. This commercial importance is created by the fact that many metal ions have desirable characteristics for these various uses, but the delivery systems for the metal ions lack specificity to target cells or do not adequately bind the metal ions. Examples of the usefulness of specific metal ions are as follows.
The usefulness of radionuclide materials in cancer therapy is disclosed in the article, Kozak et al., "Radionuclide-conjugated monoclonal antibodies: A Synthesis of Immunology, in Organic Chemistry and Nuclear Science" Trends in Biotechnology. 4(10):259-264 (1985). This article discusses the use of antibody conjugates to deliver either alpha or beta radiation. The value of alpha radiation from bismuth-212 in radionuclide therapy is further discussed in the two articles, Kozak et al., "Bismuth-212-labled anti-Tac monoclonal antibody: Alpha-particle-emitting Radionuclides as Modalities for Radioimmunotherapy" Proc. Natl. Acad. Sci. U.S.A. 83:474-478 (1986) and Gansow et al., "Generator-produced Bi-212 Chelated to Chemically Modified Monoclonal Antibody for Use in Radiotherapy" Am. Chem. So. Symposium Series 15:215-227 (1984).
Examples of other uses for chelated metal ions are disclosed in the following articles. Magerstadt et al., "Gd(DOTA): An Alternative to Gd(DPTA) as a T.sub.1,2 Relaxation Agent for NMR Imaging or Spectroscopy" Magnetic Resonance in Medicine 3:808-812 (1986), discloses the usefulness of gadolinium as a relaxation agent for NMR imaging. The article, Spirlet et al., "Structural Characterization of a Terbium(III) Complex with 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic Acid. Lanthanide Ions and the Conformation of the 14-Membered Macrocyles" Inorganic Chemistry 23(25):4278-4283 (1984), discloses the usefulness of the lanthanide chelates.
The industry is lacking an efficient process for synthesizing a DOTA chelate in high yields and that has desirable chelating qualities for numerous metal ions.